Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/51969
標題: 天然植物化合物6-shogaol與pterostilbene抑制乳癌幹細胞特性及乳癌細胞侵入轉移之研究
Dietary agents 6-shogaol and pterostilbene as inhibitors of breast cancer stem cells and suppression of invasion and metastasis in breast cancer cells
作者: 洪伯翰
Hong, Bo-Han
關鍵字: Invadopodia,6-Shogaol;Invadopodia;Pterostilbene;Cancer stem cells;Mammospheres;6-Shogaol;Pterostilbene;腫瘤幹細胞;Mammospheres
出版社: 食品暨應用生物科技學系所
引用: 王瀚揚。2009。薑超臨界二氧化碳萃取製程與薑油中 6-Shogaol 生成之探討。屏東科技大學食品科學研究所。 Goldthwaite, A. C. 2011. http://stemcells.nih.gov/info/2006report/2006chapter9.htm The national institute of health resource for stem cell research. Auerbach, W. and Auerbach, R. 1994. Angiogenesis inhibition: a review. Pharmacol. Ther. 63: 265-311. Attiga, F. A., Fernandez, P. M., Weeraratna, A. T., Manyak, M. J. and Patierno, S. R. 2000. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res. 60: 4629-4637. Abram, C. L., Seals, D. F., Pass, I., Salinsky, D., Maurer, L., Roth, T. M. and Courtneidge, S. A. 2003. The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J. Biol. Chem. 278: 16844-16851. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. and Clarke, M. F. 2003. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA. 100: 3983-3988. Aggarwal, B. B., Shishodia, S., Takada, Y., Banerjee, S., Newman, R. A., Bueso-Ramos, C. E. and Price, J. E. 2005. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin. Cancer Res. 11: 7490-7498. Artym, V. V., Zhang, Y., Seillier-Moiseiwitsch, F., Yamada, K. M. and Mueller, S. C. 2006. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res. 66: 3034-3043. Bonnet, D. and Dick, J. E. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3: 730–737. Baldassarre, M., Pompeo, A., Beznoussenko, G., Castaldi, C., Cortellino, S., McNiven, M. A., Luini, A. and Buccione, R. 2003. Dynamin participates in focal extracellular matrix degradation by invasive cells. Mol. Biol. Cell 14: 1074-1084. Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J., and Terzis, A. J. 2005. The origin of the cancer stem cell: Current controversies and new Bjerkvig, R., Johansson, M., Miletic, H. and Niclou, S. P. 2009. Cancer stem cells and angiogenesis. Semin. Cancer Biol. 19: 279-284. Balzer, E. M., Whipple, R. A., Thompson, K., Boggs, A. E., Slovic, J., Cho, E. H., Matrone, M. A., Yoneda, T. and Mueller, S. C, Martin SS. 2010. c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene 29: 6402-6408. Bhat-Nakshatri, P., Appaiah, H., Ballas, C., Pick-Franke, P., Goulet, R.. Jr., Badve, S., Srour, E. F. and Nakshatri, H. 2010. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 6: 10: 411. Colville-Nash, P. R. and Willoughby, D. A. 1997. Growth factors in angiogenesis: current interest and therapeutic potential. Mol. Med. Today. 3: 14-23. Cooper, M. K., Porter, J. A., Young, K. E. and Beachy, P. A. 1998. Teratogenmediated inhibition of target tissue response to Shh signaling. Science 280: 1603–1607. Chen, J. K., Taipale, J., Cooper, M. K., and Beachy, P. A. 2002. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16: 2743–2748. Cao, Y., Fu, Z. D., Wang, F., Liu, H. Y. and Han, R. 2005. Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants. J. Asian Nat. Prod. Res. 7: 205-213. Clarke, M. F. 2005. A self-renewal assay for cancer stem cells. Cancer Chemothery Pharmacol. Suppl 1: 64–68. Clarke, M. F. and Fuller, M. 2006. Stem cells and cancer: Two faces of eve. Cell 124: 1111–1115. Cecchinato, V., Chiaramonte, R., Nizzardo, M., Cristofaro, B., Basile, A., Sherbet, G. V., and Comi, P. 2007. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem. Pharmacol. 74: 1568–1574. Clement, V., Sanchez, P., de, Tribolet N., Radovanovic, I. and Altaba, A. 2007. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 17: 165–172. Dontu, G., Abdallah, W. M., Foley, J. M., Jackson, K. W., Clarke, M. F., Kawamura, M. J., Wicha, M. S. 2003. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17: 1253-1270. Dean, M., Fojo, T., and Bates, S. 2005. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5: 275–284. Dong, J., Peng, J., Zhang, H., Mondesire, W. H., Jian, W., Mills, G. B., Hung, M. C., Meric-Bernstam, F. 2005. Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res. 65: 1961-1972. Dorsam, R. T. and Gutkind, J. S. 2007. G-protein-coupled receptors and cancer. Nat. Rev. Cancer 7: 79-94. Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182-1186. Fidler, I. J. 2001. Angiogenic heterogeneity: regulation of neoplastic angiogenesis by the organ microenvironment. J. Natl. Cancer Inst. 93: 1040-1041. Fodde, R. and Brabletz, T. 2007. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 19: 150–158. Guzman, M. L., Neering, S. J., Upchurch, D., Grimes, B., Howard, D. S., Rizzieri, D. A., Luger, S. M. and Jordan, C. T. 2001. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98: 2301–2307. Gilbert, S. J., Duance, V. C. and Mason, D. J. 2004. Does protein kinase R mediate TNF-alpha- and ceramide-induced increases in expression and activation of matrix metalloproteinases in articular cartilage by a novel mechanism? Arthritis Res. Ther. 6: R46-R55. Guzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, D. S. and Jordan, C. T. 2005. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105: 4163–4169. Gritsko, T., Williams, A., Turkson, J., Kaneko, S., Bowman, T., Huang, M., Nam, S., Eweis, I., Diaz, N., Sullivan, D., Yoder, S., Enkemann, S., Eschrich, S., Lee, J. H., Beam, C. A., Cheng, J., Minton, S., Muro-Cacho, C. A. and Jove, R. 2006. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res. 12: 11-19. Gupta, P. B., Onder, T. T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A. and Lander, E. S. 2009. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138: 645-659. Grudzien, P., Lo, S., Albain, K. S., Robinson, P., Rajan, P., Strack, P. R., Golde, T. E., Miele, L. and Foreman, K. E. 2010. Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation. Anticancer Res. 30: 3853-3867. Huntly, B. J. and Gilliland, D. G. 2005. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat. Rev. Cancer 5: 311–321. He, B. and Jablons, D. M. 2006. Wnt signaling in stem cells and lung cancer. Ernst. Schering Found Symp. Proc. (5):27-58. Hope, C., Planutis, K., Planutiene, M., Moyer, M. P., Johal, K. S., Woo, J., Santoso, C., Hanson, J. A. and Holcombe, R. F. 2008. Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol. Nutr. Food Res. Suppl. 1:S52-61. Hurt, E. M., Kawasaki, B. T., Klarmann, G. J., Thomas, S. B. and Farrar, W. L. 2008. CD44+ CD24– prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br. J. Cancer 98: 756–765. Hwang-Verslues, W. W., Kuo, W. H., Chang, P. H., Pan, C. C., Wang, H. H., Tsai, S. T., Jeng, Y. M., Shew, J. Y., Kung, J. T., Chen, C. H., Lee, E. Y., Chang, K. J. and Lee, W. H. 2009. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers. PLoS One 4: e8377. Hsu, C. L., Hong, B. H., Yu, Y. S. and Yen, G. C. 2010. Antioxidant and anti-inflammatory effects of Orthosiphon aristatus and its bioactive compounds. J. Agric. Food Chem. 58: 2150-2156. Ichim, C. V. and Wells, R. A. 2006. First among equals: The cancer cell hierarchy. Leuk. Lymphoma 47: 2017–2027. Jiao, X., Katiyar, S., Willmarth, N. E., Liu, M., Ma, X., Flomenberg, N., Lisanti, M. P. and Pestell, R. G. 2010. c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J. Biol. Chem. 285: 8218-8226. Kelly, T., Mueller, S. C., Yeh, Y. and Chen, W. T. 1994. Invadopodia promote proteolysis of a wide variety of extracellular matrix proteins. J. Cell Physiol. 158: 299-308. Kurowska, E. M. and Manthey, J. A. 2004. Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. J. Agric. Food Chem. 52: 2879-2886. Kim, C. F., Jackson, E. L., Woolfenden, A. E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R. T. and Jacks, T. 2005. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823–835. Kim, J., Zhang, X., Rieger-Christ, K. M., Summerhayes, I. C., Wazer, D. E., Paulson, K. E., and Yee, A. S. 2006. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J. Biol. Chem. 281: 10865–10875. Kang, N. J., Lee, K. W., Lee, D. E., Rogozin, E. A., Bode, A. M., Lee, H. J. and Dong, Z. 2008. Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase. J. Biol. Chem. 283: 20664-20673. Kawasaki, B. T., Hurt, E. M., Mistree, T. and Farrar, W. L. 2008. Targeting cancer stem cells with phytochemicals. Molecular interventions 8: 174-184. Kakarala, M., Brenner, E. D., Korkaya, H., Cheng, C., Tazi, K., Ginestier, C., Liu, S., Dontu, G. and Wicha, S. M. 2009. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 122: 777-85. Kang, H. J., Lee, S. H., Price, J. E. and Kim, L. S. 2009. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 15: 223-229. Korkaya, H., Paulson, A., Charafe-Jauffret, E., Ginestier, C., Brown, M., Dutcher, J., Clouthier, S. G. and Wicha, M. S. 2009. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 7: e1000121. Kanwar, S. S., Yu, Y., Nautiyal, J., Patel, B. B. and Majumdar, A. P. 2010. The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres. Mol. Cancer 9: 212. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M. A. and Dick, J. E. 1994. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645-648. Lu, J., Ho, C. H., Ghai, G. and Chen, K. Y. 2001. Resveratrol analog, 3,4,5,4''-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 22: 321-328. Linder, S. and Aepfelbacher, M. 2003. Podosomes: adhesion hotspots of invasive cells. Trends Cell Biol. 13: 376–385. Lepourcelet, M., Chen, Y. N., France, D. S., Wang, H., Crews, P., Petersen, F., Bruseo, C., Wood, A. W. and Shivdasani, R. A. 2004. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 5: 91-102. Liu, M. C., Marshall, J. L., Pestell, R. G. 2004. Novel strategies in cancer therapeutics: targeting enzymes involved in cell cycle regulation and cellular proliferation. Curr. Cancer Drug Targets 4: 403-424. Liu, S., Dontu, G. and Wicha, M. S. 2005. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 7: 86–95. Lua, B. L. and Low, B. C. 2005. Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett. 579: 577-585. Lee, J., Kotliarova, S., Kotliarov, Y., Li, A., Su, Q., Donin, N. M., Pastorino, S., Purow, B. W., Christopher, N., Zhang, W., Park, J. K. and Fine, H. A. 2006. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9: 391-403. Levy, A. S., Simon, O., Shelly, J. and Gardener, M. 2006. 6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund''s adjuvant. BMC Pharmacol. 6: 12. Li, F., Tiede, B., Massagué, J. and Kang, Y. 2007. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 17: 3-14. Liu, S., Dontu, G., Mantle, I. D., Patel, S., Ahn, N. S., Jackson, K. W., Suri, P. and Wicha, M. S. 2006. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66: 6063-6071. Lai, C. S., Li, S., Chai, C. Y., Lo, C. Y., Ho, C. T., Wang, Y. J. and Pan, M. H. 2007. Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3'',4''-hexamethoxy- flavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice. Carcinogenesis 28: 2581-2588. Li, C., Heidt, D. G., Dalerba, P., Burant, C. F., Zhang, L., Adsay, V., Wicha, M., Clarke, M. F. and Simeone, D. M. 2007. Identification of pancreatic cancer stem cells. Cancer Res. 67: 1030–1037. Linder, S. 2007. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 17: 107-117. Li, Y., Zhang, T., Korkaya, H., Liu, S., Lee, H. F., Newman, B., Yu, Y., Clouthier, S. G., Schwartz, S. J., Wicha, M. S. and Sun, D. 2010. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin. Cancer Res. 16: 2580-2590. Ling, H., Yang, H., Tan, S. H., Chui, W. K. and Chew, E. H. 2010. 6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor-κB activation. Br. J. Pharmacol. 161: 1763-1777. Li, J. and Zhou, B. P. 2011. Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11: 49. Monsky, W. L., Kelly, T., Lin, C. Y., Yeh, Y., Stetler-Stevenson, W. G., Mueller, S. C. and Chen, W. T. 1993. Binding and localization of M(r) 72,000 matrix metalloproteinase at cell surface invadopodia. Cancer Res. 53(13): 3159-3164. Munaut, C., Noël, A., Hougrand, O., Foidart, J. M., Boniver, J. and Deprez, M. 2003. Vascular endothelial growth factor expression correlates with matrix metalloproteinases MT1-MMP, MMP-2 and MMP-9 in human glioblastomas. Int. J. Cancer. 106: 848-855. Miyata, Y., Sato, T., Yano, M. and Ito, A. 2004. Activation of protein kinase C betaII/epsilon-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin. Mol. Cancer Ther. 3: 839-847. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715. Nakahara, H., Howard, L., Thompson, E. W., Sato, H., Seiki, M., Yeh, Y. and Chen, W. T. 1997. Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc. Natl. Acad. Sci. U S A. 94: 7959-7964. Orsulic, S., Huber, O., Aberle, H., Arnold, S. and Kemler, R. 1999. E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. J. Cell Sci. 112: 1237-1245. O''Leary, K. A., de Pascual-Tereasa, S., Needs, P. W., Bao, Y. P., O''Brien, N. M. and Williamson, G. 2004. Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat. Res. 551: 245-254. Osiak, A. E., Zenner, G. and Linder, S. 2005. Subconfluent endothelial cells form podosomes downstream of cytokine and RhoGTPase signaling. Exp. Cell Res. 307: 342-353. O’Brien, C. A., Pollett, A., Gallinger, S. and Dick, J. E. 2007. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110. Oser, M., Yamaguchi, H., Mader, C. C., Bravo-Cordero, J. J., Arias, M., Chen, X., Desmarais, V., van Rheenen, J., Koleske, A. J. and Condeelis, J. 2009. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J. Cell Biol. 186: 571-587. Omene, C. O., Wu, J. and Frenkel, K. 2011. Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells. Invest. New Drugs. Pálmer, H. G., González-Sancho, J. M., Espada, J., Berciano, M. T., Puig, I., Baulida, J., Quintanilla, M., Cano, A., de Herreros, A. G., Lafarga, M. and Muñoz, A. 2001. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J. Cell Biol. 154: 369-387. Pardal, R., Clarke, M. F., and Morrison, S. J. 2003. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 3: 895–902. Pari, L. and Satheesh, M. A. 2006. Effect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin- and nicotinamide- induced diabetic rats. Life Sci. 79: 641-645. Patrawala, L., Calhoun, T., Schneider-Broussard, R., Li, H., Bhatia, B., Tang, S., Reilly, J. G., Chandra, D., Zhou, J., Claypool, K., Coghlan, L. and Tang, D. G. 2006. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 25: 1696-1708. Polyak, K. and Hahn, W.C. 2006. Roots and stems: Stem cells in cancer. Nat. Med. 12: 296–300. Pan, M. H., Lai, Y. S., Lai, C. S., Wang, Y. J., Li, S., Lo, C. Y., Dushenkov, S. and Ho, C. T. 2007. 5-Hydroxy-3,6,7,8,3'',4''-hexamethoxyflavone induces apoptosis through reactive oxygen species production, growth arrest and DNA damage-inducible gene 153 expression, and caspase activation in human leukemia cells. J. Agric. Food Chem. 55: 5081-5091. Peacock, C. D., Wang, Q., Gesell, G. S., Corcoran-Schwartz, I. M., Jones, E., Kim, J., Devereux, W. L., Rhodes, J. T., Huff, C. A., Beachy, P. A., Watkins, D. N. and Matsui, W. 2007. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl. Acad. Sci. U. S. A. 104: 4048-4053. Pan, M. H., Hsieh, M. C., Kuo, J. M., Lai, C. S., Wu, H., Sang, S. and Ho, C. T. 2008. 6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression. Mol. Nutr. Food Res. 52: 527-537. Priego, S., Feddi, F., Ferrer, P., Mena, S., Benlloch, M., Ortega, A., Carretero, J., Obrador, E., Asensi, M. and Estrela, J. M. 2008. Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism. Mol. Cancer Ther. 7: 3330-3342. Pan, M. H., Chiou, Y. S., Chen, W. J., Wang, J. M., Badmaev, V. and Ho, C. T. 2009. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis 30: 1234-1242. Pichot, C. S., Hartig, S. M., Xia, L., Arvanitis, C., Monisvais, D., Lee, F. Y., Frost, J .A. and Corey, S. J. 2009. Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. British Journal of Cancer 101: 38 – 47. Pinilla, S., Alt, E., Abdul Khalek, F. J., Jotzu, C., Muehlberg, F., Beckmann, C. and Song, Y. H. 2009. Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. Cancer Lett. 284: 80-85. Polyak, K. and Weinberg, R. A. 2009. Transitions between epithelial andmesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9: 265–273. Prud''homme, G. J., Glinka, Y., Toulina, A., Ace, O., Subramaniam, V., and Jothy, S. 2010. Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLoS One 5: e13831. Quintana, E., Shackleton, M., Sabel, M. S., Fullen, D. R., Johnson, T. M. and Morrison, S. J. 2008. Efficient tumour formation by single human melanoma cells. Nature 456: 593-598. Qiu, P., Dong, P., Guan, H., Li, S., Ho, C.T., Pan, M. H., McClements, D. J. and Xiao, H. 2010. Inhibitory effects of 5-hydroxy polymethoxy- flavones on colon cancer cells. Mol. Nutr. Food Res. 2: S244-252. Reya, T., Morrison, S. J., Clarke, M. F. and Weissman, I. L. 2001. Stem cells, cancer, and cancer stem cells. Nature 414: 105-111. Redondo-Muñoz, J., Escobar-Díaz, E., Samaniego, R., Terol, M. J., García-Marco, J. A. and García-Pardo, A. 2006. MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by alpha4beta1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration. Blood 108: 3143-3151. Sherr, C. J. Mammalian G1 cyclins and cell cycle progression. 1995. Proc. Assoc. Am. Physicians. 107:181-186. Sherr, C. J. Cancer cell cycles. Science 1996. 274:1672-1677. Soleas, G. J., Diamandis, E. P. and Goldberg, D. M. 1997. Resveratrol: a molecule whose time has come? And gone? Clin. Biochem. 30: 91-113. Sherr, C. J. and Roberts, J. M. 1999. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13: 1501-1512. Sadzuka, Y., Sugiyama, T. and Sonobe, T. 2000. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Toxicol. Lett. 114: 155–162. Stamenkovic, I. 2000. Matrix metalloproteinases in tumor invasion and metastasis. Semin. Cancer Biol. 10: 415-433. Small, J. V., Stradal, T., Vignal, E. and Rottner, K. 2002. The lamellipodium: where motility begins. Trends Cell Biol. 12: 112-120.Sounni, N. E., Devy, L., Hajitou, A., Frankenne, F., Munaut, C., Gilles, C., Deroanne, C., Thompson, E. W., Foidart, J. M. and Noel, A. 2002. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J. 16: 555-64. Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J. and Dirks, P. B. 2003. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63: 5821–5828. Simoni, D., Roberti, M., Invidiata, F. P, Aiello, E., Aiello, S., Marchetti, P., Baruchello, R., Eleopra, M., Di Cristina, A., Grimaudo, S., Gebbia, N., Crosta, L., Dieli, F. and Tolomeo, M. 2006. Stilbene-based anticancer agents: resveratrol analogues active toward HL60 leukemic cells with a non-specific phase mechanism. Bioorg. Med. Chem. Lett. 16: 3245-3248. Suh, N., Paul, S., Hao, X., Simi, B., Xiao, H., Rimando, A. M. and Reddy, B. S. 2007. Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats. Clin. Cancer Res. 13: 350-355. Saini, V. and Shoemaker, R. H. 2009. Potential for therapeutic targeting of tumor stem cells. Cancer sci. 101: 16-21. Singh, A. and Settleman, J. 2010. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29: 4741-4751. So, J. Y., Lee, H. J., Smolarek, A. K., Paul, S., Wang, C. X., Maehr, H., Uskokovic, M., Zheng, X., Conney, A. H., Cai, L., Liu, F. and Suh, N. 2010. A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol Pharmacol. 79: 360-367. Takahashi-Yanaga, F., Mori, J., Matsuzaki, E., Watanabe, Y., Hirata, M., Miwa, Y., Morimoto, S. and Sasaguri, T. 2006. Involvement of GSK-3beta and DYRK1B in differentiation-inducing factor-3-induced phosphorylation of cyclin D1 in HeLa cells. J. Biol. Chem. 281: 38489-38497. Tatin, F., Varon, C., Génot, E. and Moreau, V. 2006. A signalling cascade involving PKC, Src and Cdc42 regulates podosome assembly in cultured endothelial cells in response to phorbol ester. J. Cell Sci. 119: 769-781. Tehrani, S., Faccio, R., Chandrasekar, I., Ross, F. P. and Cooper, J. A. 2006. Cortactin has an essential and specific role in osteoclast actin assembly. Mol. Biol. Cell. 17: 2882-2895. Tang, C., Ang, B. T. and Pervaiz, S. 2007. Cancer stem cell: target for anti-cancer therapy. FASEB J. 21: 3777-3785. Takehara, M., Hoshino, T., Namba, T., Yamakawa, N. and Mizushima, T. 2011. Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice. Biochem. Pharmacol. 81: 1124-1135. Wattenberg, L. W. 1993. Prevention-therapy-basic science and the resolution of the cancer problem. Cancer Res. 53: 5890-5896. Woo, J. H., Lim, J. H., Kim, Y. H., Suh, S. I., Min, D. S., Chang, J. S., Lee, Y. H., Park, J. W. and Kwon, T. K. 2004. Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction. Oncogene 23: 1845-1853. Webb, B. A., Zhou, S., Eves, R., Shen, L., Jia, L. and Mak, A. S. 2006. Phosphorylation of cortactin by p21-activated kinase. Arch. Biochem. Biophys. 456: 183-193. Weaver, A. M. 2006. Invadopodia: specialized cell structures for cancer invasion. Clin. Exp. Metastasis 23: 97-105. Woodward, W. A., Chen, M. S., Behbod, F., Alfaro, M. P., Buchholz, T. A. and Rosen, J. M. 2007. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc. Natl. Acad. Sci. USA 104: 618-623. Weng, C. J., Chau, C. F., Hsieh, Y. S., Yang, S. F. and Yen, G. C. 2008. Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. Carcinogenesis 29: 147-156. Weng, C. J., Wu, C. F., Huang, H. W., Ho, C. T. and Yen, G.C. 2010. Anti-invasion effects of 6-shogaol and 6-gingerol, two active components in ginger, on human hepatocarcinoma cells. Mol. Nutr. Food Res. 54: 1618-1627. Yoshimizu, N., Otani, Y., Saikawa, Y., Kubota, T., Yoshida, M., Furukawa, T., Kumai, K., Kameyama, K., Fujii, M., Yano, M., Sato, T., Ito, A. and Kitajima, M. 2004. Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol. Ther. 11: 95-101. Yamaguchi, H., Lorenz, M., Kempiak, S., Sarmiento, C., Coniglio, S., Symons, M., Segall, J., Eddy, R., Miki, H., Takenawa, T. and Condeelis, J. 2005. Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J. Cell Biol. 168: 441-452. Yoshio, T., Morita, T., Kimura, Y., Tsujii, M., Hayashi, N. and Sobue, K. 2007. Caldesmon suppresses cancer cell invasion by regulating podosome/invadopodium formation. FEBS Lett. 581: 3777-3782. Yang, Y. T., Weng, C. J., Ho, C. T. and Yen, G. C. 2009. Resveratrol analog-3,5,4''-trimethoxy-trans-stilbene inhibits invasion of human lung adenocarcinoma cells by suppressing the MAPK pathway and decreasing matrix metalloproteinase-2 expression. Mol. Nutr. Food Res. 53: 407-416. Yeh, C. T., Wu, C. H. and Yen, G. C. 2010. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol. Nutr. Food Res. 54: 1285-1295. Yeung, T. M., Gandhi, S. C., Wilding, J. L., Muschel, R. and Bodmer, W. F. 2010. Cancer stem cells from colorectal cancer-derived cell lines. Proc. Natl. Acad. Sci. USA 107: 3722-3727. Yao, H., Ashihara, E. and Maekawa, T. 2011. Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin. Ther. Targets [Epub ahead of print] Zeng, H. and Combs, G.F., Jr. 2007. Selenium as an anticancer nutrient: Roles in cell proliferation and tumor cell invasion. J. Nutr. Biochem. 19: 1-7. Zhou, J., Zhang, H., Gu, P., Bai, J., Margolick, J.B., and Zhang, Y. 2008. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stemlike cells. Breast Cancer Res. Treat. 111: 419-427.
摘要: 
乳癌位居世界癌症死因之第五位,具有高度轉移性、容易復發而難以根治,癌症轉移係指癌細胞為了得到更多養分,侵入到周遭組織中,甚至進入循環系統之過程。癌症之復發被認為與癌幹細胞 (cancer stem cells, CSCs)有關,一般而言,幹細胞 (stem cell)具有發展分化成許多不同細胞的能力,然而不正常的幹細胞則會成長為不正常的細胞群,像是乳癌幹細胞 (breast cancer stem cells, BCSCs)會生長擴張成具有抗藥性的細胞群,進一步限制目前癌症的治療功效。乳癌幹細胞可利用表面抗原CD44+/CD24-/low及其群聚成mammospheres之特性來做辨認。本研究目的為探討天然植物化合物是否能抑制乳癌細胞之侵入與移行,以及其對於MCF7分離之乳癌幹細胞是否具有抑制活性與未來可否能輔助化學治療以根治乳癌。植物化合物(phytochemicals)對人體有許多益處且相較於藥物較無副作用,同時近年來其抗癌活性亦被廣泛探討。故本研究首先評估兩種天然植物化合物,6-shogaol(6-S)與pterostilbene(Pet)對乳癌細胞株MDA-MB231及T47D細胞之matrix metalloproteinase(MMPs)活性、細胞移行與侵入試驗。結果發現6-S與Pet分別於10及25uM濃度即能有效抑制MDA-MB231及T47D細胞之MMP-2與MMP-9活性、顯著降低其細胞侵入與移行現象。Invadopodia是在侵入性癌細胞中特有的一種細胞結構,為癌細胞侵入過程中降解基質的主要角色,其組成之核心蛋白包含cortactin與MT1-MMP。進一步分析Invadopodia核心蛋白cortactin與MT1-MMP蛋白質表現。實驗結果顯示,6-S及Pet 於2小時抑制MDA-MB231細胞cortactin與MT1-MMP之蛋白表現。
本研究進一步以五種天然植物化合物: 6-gingerol (6-G)、6-S、5-hydroxy-3,6,7,8,3‘,4‘-hexamethoxyflavone (5-Hs)、nobiletin (Nol)和Pet分別測定乳癌細胞株MCF7及其分離之乳癌幹細胞 (BCSCs)之細胞存活率,結果顯示,在處理劑量25與50uM時,6-S及Pet能專一性毒殺乳癌幹細胞,同時對於MCF7較不具毒性。以6-S和Pet分別測定其對於mammospheres以及結合化療藥物paclitaxel對乳癌幹細胞分化群之存活率影響。結果顯示6-S及Pet 和乳癌幹細胞共培養72小時,可顯著抑制mammospheres形成,且具有輔助低劑量臨床化療藥物paclitaxel降低乳癌幹細胞分化群存活之效用。因此,6-S及Pet能減少乳癌幹細胞群存活、mammospheres群聚數與體積以及輔助化療藥物之功效。許多訊息調控路徑像是hedgehog、PI3K/Akt和Wnt/b-catenin與細胞自我更新、正常器官幹細胞或胚胎幹細胞存活相關。而最近文獻中也指出,這些訊息路徑也可能參與維持CD44+/CD24-/low乳癌幹細胞之stemness特性。進一步探討化合物之作用機制是否可以調控這些訊息傳遞路徑,結果發現6-S與Pet皆能於72小時有效降低細胞表面抗原CD44表現量。其中6-S和Pet可提升b-catenin降解活性,而減少下游c-Myc、cyclinD1蛋白質表現,其主要是透過抑制hedgehog蛋白質表現、Akt及GSK3B之磷酸化,而降低b-catenin轉錄程度。由以上結果得知,6-S與Pet能抑制乳癌細胞侵入移行之程度並且透過調節b-catenin磷酸化表現而降低CD44表現,而抑制mammospheres生成,影響乳癌幹細胞特性之維持。
綜合上述,6-S和Pet不僅具有降低癌細胞轉移之抗癌能力,同時也能作用於抑制其幹細胞特性,因此推測6-S及Pet 可能有潛力作為化療藥物之佐劑。

Breast cancer, the fifth leading cause of malignancy-related death in the world, is hard to eradicate because of the highly metastasis and easily relapse. Tumor metastases are defined as the invasion of cancer cells into their surrounding tissues, or even to the circulatory system, when the cells lack nutrients. The relapses of cancer are typically considered to be related to cancer stem cells (CSCs). Stem cells have the ability to differentiate into different types of cells. Consequently, abnormal stem cells can develop into a group of abnormal cells. For instance, breast cancer stem cells can grow and develop into therapy-resistant colonies and therefore limit the efficiency of the modern chemotherapy. Breast cancer stem cells (BCSCs) could be identified by special cell surface markers CD44+/CD24-/low and nonadherent spherical cell clusters termed mammospheres. Recently, phytochemicals have been widely discussed for their chemopreventive activities because they offered the similar benefits but with less toxicity than the clinical chemotherapy. The aim of this study was to determine the anti-metastasis effects of phytochemicals on two different breast cancer cell lines, MDA-MB231 and T47D, and the potential anti-cancer effect on target BCSCs, isolated from the breast cancer MCF7 cell line. 6-Shogaol (6-S) and pterostilbene (Pet), two nature compounds, were used to investigate their inhibitory effects on cancer invasion and migration. 6-S and Pet were found to have the ability to inhibit MMP-2/9 activities, cell migration and invasion of MDA-MB231 cells for 24 h at 25 uM and 50 uM. Invadopodia, special structures mainly consist of core protein cortactin and MT1-MMP on cancer cell membranes, are found to assist malignant cancer cells in their invasion and migration into other tissues. This study also indicated that 6-S and Pet significantly reduced the protein expressions of cortactin and MT1-MMP in MDA-MB231 cells for 2 h at 10 uM and 25uM.
Five phytochemicals, including 6-gingerol (6-G), 6-S, 5-hydroxy-3,6,7,8,3‘,4‘-hexamethoxyflavone (5-Hs), nobiletin (Nol) and Pet were used to investigate their effects on cell viabilities of MCF7 cells and BCSCs. The results showed that 6-S and Pet were able to selectively kill BCSCs but not MCF7 cells at 25 and 50 uM. These two effective compounds, 6-S and Pet were then used to investigate their effects on mammospheres formations in BCSCs. The results showed that 6-S and Pet inhibited the formation of mammospheres after co-incubation with BCSCs for 72 h, respectively. Furthermore, 6-S and Pet were applied to evaluate cell viabilities when combined with paclitaxel in differentiated BCSCs. Our results showed that both 6-S and Pet assisted paclitaxel to reduce cell viability in differentiated BCSCs. Therefore, treatments with 6-S and Pet could reduce cell viability and mammospheres formations in BCSCs and assist chemotherapy to inhibit cell survival in differentiated BCSCs. In the previous studies, many signaling transductions like hedgehog, Notch, PI3K/Akt and Wnt/b-catenin were found to be highly related to the survival and self-renewal of stem cells. Moreover, the recent researches showed these signaling molecules are also involved in the CD44 expression and the stemness maintenance of cancer stem cells. 6-S and Pet effectively reduced the CD44 expression in the BCSCs after 72 h co-incubation. Immunoblotting analysis showed that 6-S and Pet inhibited cyclinD1, c-Myc and GSK3B phosphorylation, but increased b-catenin phosphorylation through inhibiting hedgehog and Akt phosphorylation in the BCSCs.
These data suggest that 6-S and Pet work not only by reducing cell metastasis but also by inhibiting stemness of the malignant cancer stem cells. In conclusion, 6-S and Pet may have the potential to be adjuvants of chemotherapy.
URI: http://hdl.handle.net/11455/51969
其他識別: U0005-1808201110041900
Appears in Collections:食品暨應用生物科技學系

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.